Pyridyl-pyridazinone and pyridyl-pyrazolinone compounds and their use in the treatment of congestive heat failure

ABSTRACT

This invention relates to pyridyl-pyrazolinone compounds of the formula ##STR1## uses of said compounds as cardiotonic agents including methods for increasing cardia contractility and the treatment of congestive heart failure, pharmaceutical compositions including the same and methods for the preparation thereof.

This is a divisional application of application Ser. No. 011,490 U.S.Pat. No. 4,826,835 which is a continuation-in-part of application Ser.No. 790,426 filed Oct. 23, 1985, U.S. Pat. No. 4,783,463.

FIELD OF INVENTION

This invention relates to pyridazinone and pyrazolinone compounds usefulas cardiotonic agents for the treatment of congestive heart failure, totheir preparation and to pharmaceutical compositions including the same.

REPORTED DEVELOPMENTS

Congestive heart failure is a life threatening condition in whichmyocardial contractility is depressed such that the heart is unable toadequately pump the blood returning to it. Normal pathologic sequelaeinclude decreased cardiac output, venous pooling, increased venouspressure, edema, increased heart size, increased myocardial walltension, and eventually cessation of contractility. Digitalis glycosideshave long been used to increase myocardial contractility and reverse thedetrimental changes seen in congestive heart failure. More recently,dopamine, dobutamine, and amrinone have been used to provide necessaryinotropic support for the failing heart.

Other reported inotropic drugs include the substituted pyridazinonesdisclosed in U.S. Pat. No. 4,353,905, wherein the 6-position of thepyridazinone is substituted by 4-imidazolyl phenyl, and in U.S. Pat.Nos. 4,397,854 and 4,404,203, where the 6-position of the pyridazinoneis substituted by various substituted phenyl groups.

The prior art does not disclose pyridazinones substituted in the6-position by a 1-imidazolyl pyridyl group.

The present invention relates to a class of novel pyridazinone andpyrazolinone compounds which exhibit cardiotonic activity in humans andmammals.

SUMMARY OF INVENTION

This invention relates to the compounds described by the Formula I##STR2## wherein: Het is imidazol-1-yl or 1,2,4-triazol-1-yl;

py is 2-, 3- or 4-pyridyl

x is 0 or 1;

R_(n) is hydrogen, alkyl, aralkyl, acyl, carbalkoxy, carbamyl,carbalkoxyalkyl, hydroxyalkyl, alkoxyalkyl or amidino;

R₁ and R₂ are each independently hydrogen, alkyl or aralkyl;

R₁ groups on vicinal carbon atoms may together form a carbon-carbondouble bond when R_(n) is hydrogen and x=1; and

R is hydrogen or --(CH₂)_(y) --Y where y is 1-3 and Y is hydrogen,--O--R.sub.α, --S--R.sub.α or ##STR3## where R.sub.α is hydrogen, alkylor acyl and;

R.sub.β is hydrogen or alkyl; and

R.sub.α and R.sub.β together may form a 3-7 membered ring which may alsocontain 0-2 additional hetero atoms selected from N, O and S; or apharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutical compositions for use inincreasing cardiac contractility in humans and to the uses of thesecompounds in the treatment of congestive heart failure in humans andother mammals.

DETAILED DESCRIPTION

Certain of the compounds of Formula I may exist in enolic or tautomericforms, and all of these forms are considered to be included within thescope of this invention.

The compounds of this invention which have particular usefulness ascardiotonic agents are described by the formulae below. ##STR4## whereinR and R_(n) are as described above and X is CH or N.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

"Alkyl" means a saturated aliphatic chain, either branched or straight,including up to about 6 carbon atoms.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl,isopropyl, butyl, sec-butyl, and tert-butyl.

"Aralkyl" means an alkyl group substituted by an aryl radical. Thepreferred aralkyl groups are benzyl or phenethyl.

"Acyl" means an organic radical derived from an organic acid by theremoval of its hydroxyl group. Preferred acyl groups are acetyl,propionyl, benzoyl, etc.

"Alkoxy" refers to a loweralkyl--O-- group.

The term "halo" means a halogen. Preferred halogens include chloride,bromide, and fluoride.

"2-pyridyl" means a pyridyl ring bonded to the pyridazinone orpyrazolinone ring described in Formula I at the pyridyl carbon ortho tothe nitrogen atom.

"3-pyridyl" means a pyridyl ring bonded to the pyridazinone orpyrazolinone ring described in Formula I at the pyridyl carbon meta tothe nitrogen atom.

"4-pyridyl" means a pyridyl ring bonded to the pyridazinone orpyrazolinone ring described in Formula I at the pyridyl carbon para tothe nitrogen atom.

"Het" means imidazol-1-yl or 1,2,4-triazol-1-yl.

The compounds of this invention may be useful in the form of the freebase, if a basic group is present, in the form of salts and as ahydrate, and all forms are within the scope of the invention. Acidaddition salts may be formed and are simply a more convenient form foruse; and in practice, use of the salt form inherently amounts to use ofthe base form. The acids which can be used to prepare the acid additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically acceptable salts, that is, salts whoseanions are non-toxic to the animal organism in pharmaceutical doses ofthe salts, so that the beneficial cardiotonic properties inherent in thefree base are not vitiated by side effects ascribable to the anions.Although pharmaceutically acceptable salts of said basic compound arepreferred, all acid addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as, for example, when the salt is formed only forpurposes of purification and identification, or when it is used as anintermediate in preparing a pharmaceutically acceptable salt by ionexchange procedures. Pharmaceutically acceptable salts within the scopeof the invention are those derived from the following acids: mineralacids such as hydrochloric acid, sulfuric acid, phosphoric acid andsulfamic acid; and organic acids such as acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like. The correspondingacid addition salts comprise the following: hydrochloride, sulfate,phosphate, sulfamate, acetate, citrate, lactate, tartarate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate, respectively.

The acid addition salts of the compounds of this invention are preparedeither by dissolving the free base in aqueous or aqueous-alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution.

Compounds within the scope of Formula I may be prepared in accordancewith one or more of the following reaction sequences.

The 3-pyridyl compounds of Formula I may be prepared from the morpholinocyano intermediate, Formula IV below, according to the reactionsequences shown in Schemes I and II below.

The 2- and 4-pyridyl compounds of Formula I may be prepared using theanalogous 2- and 4-pyridyl intermediates. ##STR5##

When x in Formula I is 0, the anion of intermediate IV may be alkylatedwith an alkyl ester of a haloacetic acid and the resulting alkylationproduct V treated with hydrazine affording the cyclized end product, asshown in Scheme I above.

When x in Formula I is 1, the 6-membered ring may be prepared byreacting the anion of intermediate IV with the ester of an alpha,beta-unsaturated carboxylic acid, thereby forming the 1,4-additionproduct VI. Reaction of the addition product with a hydrazine forms thecyclized end product, as shown in Scheme II below. ##STR6##

The anion of the intermediate IV may be prepared using a strong base inan aprotic polar solvent such as THF or DMF. The base may be the lithiumanion of diisopropyl amine in THF, sodium methoxide in THF or sodiumhydride in DMF.

The intermediate IV may be prepared according to the reaction sequencedepicted in Scheme III below. ##STR7##

2-Halo nicotinic acid, methyl ester may be treated with imidazole andsodium hydride affording the 2-imidazolyl derivative. The esterfunctionality is reduced to the alcohol followed by oxidation to thealdehyde. The resulting 2-imidazolyl-5-formyl pyridine is refluxed withp-toluene sulfonic acid and morpholine in THF followed by treatment withpotassium cyanide. The cyano morpholino intermediate IV results.

Hydrolysis of the cyano-morpholino propionate or butyrate described asformulae V and VI to the corresponding keto acid VII followed bytreatment with an amine of the formula ##STR8## and formaldehyde resultsin the corresponding Mannich base. This may then be reacted with ahydrazine to obtain the desired R-substituted product. This is describedin Scheme IV. ##STR9##

When R is --O--R.sub.α the enolate anion of VII is treated withethylformate to generate VIII which upon reduction and ring closure witha hydrazine gives the desired product. ##STR10## where x is 0 or 1.

The corresponding thio --S--R compound can be prepared by conversion ofhydroxymethyl intermediate into the corresponding mesylate, followed bytreatment of the latter with a thiol and DBU in benzene. Treatment ofthe resulting sulfide with a hydrazine produces the thiomethylderivative of Formula I. This is described below. ##STR11##

The following are illustrative examples of the preparation of thecompounds of the present invention.

EXAMPLE I PREPARATION OF4,5-DIHYDRO-6-[6-(1H-IMIDAZOL-1-YL)PYRID-3-YL]-5-METHYL-3-(2H)-PYRIDAZINONEStep 1. 6-Chloro nicotinic acid, methyl ester

An ethereal solution of CH₂ N₂ (0.1 mole) is added to a suspension of6-chloro nicotinic acid (15 g) in CH₂ Cl₂ until bubbling ceases. Thereaction mixture is stirred overnight, evaporated and dried in vacuoaffording the desired product as a tan solid used in the next stepwithout further purification.

Step 2. 6-1H-imidazol-1-yl-nicotinic acid, methyl ester

A solution of the methyl ester obtained in Step 1. above (16.29 g) inDMF is added dropwise to a DMF suspension of sodium imidazole [preparedfrom NaH (4.19 g) and imidazole 6.49 g)] at RT. The reaction mixture isheated to 120° C. for nineteen hours. The cooled reaction mixture ispartitioned between water and chloroform, the organic layer separated,washed with water, dried over Na₂ SO₄, filtered, evaporated, andresidual DMF removed under high vacuum yielding the desired product as atan solid which is recrystalized from methanol (M.P. 183°-184.5° C.)before use in the next step.

Step 3. 2-1H-imidazol-1-yl-5-hydroxymethylpyridine

NaBH₄ (37.82 g) is added portionwise to a suspension of the imidazolylester of Step 2. above (9.98 g) in methanol at about 0.° C. The reactionmixture is heated to reflux for 71/2 hours, allowed to cool and stand 15hours. Water (75 ml) is added, and the quenched reaction mixtureevaporated, affording a solid residue which is suspended in water,extracted with chloroform dried over Na₂ SO₄, filtered and evaporated,recrystallized (CHCl₃), affording the desired product as a white solid.M.P.=128.5°-130° C.

Step 4. 2-1H-imidazol-1-yl-5-formylpyridine

MnO₂ (18.17 g) is added to a solution of the hydroxy methyl compound ofStep 3. above (6.1 g) in CHCl₃, and the resulting reaction mixtureheated to reflux for 22 hours, allowed to cool, filtered, and theorganic layer evaporated affording the desired product as a white solidused in the next step without further purification. M.P.=139.5°-140.5°C.

Step 5. 6-[1H-imidazol-1-yl]-α-cyano-α-N-morpholino-3-picoline

The formyl compound of Step 4 above (5.0 g) is added to a solution ofpTSA monohydrate (5.95 g), THF (30.0 ml) and morpholine (5.44 g). Thereaction mixture is heated to reflux for 2 hours, cooled and a solutionof KCN (2.54 g) in water (4.5 ml) added. Refluxing is continuedovernight, after which the reaction mixture is cooled and partitionedbetween water and chloroform. The chloroform extract is washed withaqueous sodium bisulfite, brine, dried over Na₂ SO₄, filtered andevaporated affording the desired product as a yellow solid used in thenext step without further purification.

Step 6. ethyl,4cyano-4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-methyl-4-N-morpholinobutyrate

A solution of the morpholinyl-cyano methyl compound obtained in Step 5.above (2.0 g) in THF (27 ml) is added dropwise to a solution of lithiumdiisopropyl amide (0.7 ml of amine) in THF (20 ml) and the reactionmixture is stirred 2.5 hours at -78° C. HMPA (1.34 g) and a solution ofLiBr (0.72 g) and ethyl crotonate (0.94 g) in THF (13.0 ml) are addeddropwise to the reaction mixture at -78° C. and stirring continued at RTfor 40 hours. The mixture is diluted with ether, quenched with saturatedNH₄ Cl (50 ml), extracted with CHCl₃, washed with brine, dried over Na₂SO₄, filtered and evaporated, affording an oil which is dissolved inethyl acetate and chromatographed (silica gel), eluting with a mixtureof ethyl acetate:hexane (85:15). The purified fractions are combined andevaporated to yield the desired product as a yellow solid used in thenext step without further purification.

Step 7.4,5-dihydro-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]-5-methyl-3(2H)-pyridazinone

Hydrazine monohydrate (1.85 g) is added to a solution of the productobtained in Step 6. above (2.39 g) in ethanol (20 ml). The reactionmixture is heated to reflux for 94 hours, allowed to stand at RT,filtered and the yellow precipitate washed in ethanol and dried,affording the desired product. M.P.=207°-209.5° C.

EXAMPLE II PREPARATION OF4,5-DIHYDRO-6-[6-(1H-IMIDAZOL-1-YL)PYRID-3-YL]-3(2H)-PYRIDAZINONEStep 1. ethyl, 4-cyano-4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-N-morpholinobutyrate

Potassium hydroxide (0.18 g) is added to a stirring solution ofα-cyano-6-(1H-imidazol-1-yl)-α-morpholino-3-picoline (3.0 g) inanhydrous THF (120 ml). The reaction mixture is stirred for 10 minutesand ethyl acrylate (6.03 g) is added to the mixture. Stirring iscontinued for 2 hours at RT after which a second portion of KOH (0.18 gin 0.5 ml ethanol) and ethyl acrylate 6.03 g) is added. Stirring of thereaction mixture is continued at RT for 19 hours, the mixture isconcentrated in vacuo, the oily residue covered with toluene,concentrated in vacuo, the residue dissolved in CHCl₃, filtered, and thefiltrate concentrated in vacuo yielding an oil. The oil is dissolved inethyl acetate and chromatographed (silica gel), eluting fractions withethyl acetate. The pure fractions are combined and concentrated invacuo, resulting in the desired product as an amber oil.

Step 2.4,5-dihydro-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-(2H)-pyridazinone

Hydrazine monohydrate (0.41 g) is added to a stirred solution of theproduct obtained in Step 1. above (2.5 g) in ethanol (50 ml) and thereaction mixture refluxed for 67 hours. A second portion of hydrazinemonohydrate (0.41 g) is added to the refluxing reaction mixture andrefluxing continued for an additional 4 hours. The cooled mixture isconcentrated, and suspended in methanol. Silica gel (8 g; 250-400 mesh)is added and the resulting suspension is concentrated in vacuo. Thesilica gel residue is stirred in anhydrous ether, concentrated in vacuo,layered onto a silica gel column, and eluted with a mixture ofmethanol:ethyl acetate (5:95). The slower purified fractions arecombined, concentrated in vacuo and the resulting solid dried under highvacuum overnight, affording the desired product as a yellow solid.M.P.=276.5°-278° C., The desired structure is confirmed by IR analysisand by elemental analysis for C₁₂ H₁₁ N₅ O from the following data.Calculated: C (59.74), H (4.6), N (29.03); Found: C (59.31), H (4.48), N(28.63).

EXAMPLE III PREPARATION OF3,4-DIHYDRO-5-[6-(1H-IMIDAZOL-1-YL)PYRID-3-YL]-3-PYRAZOLINONE Step 1.ethyl, 3-cyano-3-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-N-morpholinopropionate

A solution of α-cyano-6-[1H-imidazol-1-yl]-α-N-morpholino-3-picoline (1g) in DMF (3 ml) is added dropwise to a suspension of sodium hydride(0.164 g) in DMF (3 ml) under nitrogen, and stirred at RT for 2 hours.Ethyl bromoacetate (0.62 g) in DMF (3 ml) is added to the mixture, andstirring continued at a lowered temperature (-10° to -15° C.) for aboutone hour. The reaction mixture is poured into ice, the organic layerextracted with CHCl₃, the chloroform extract washed with brine, driedover Na₂ SO₄, filtered, evaporated, and the DMF removed under highvacuum, affording an oil. The oil is chromotographed (silica gel),eluting fractions with a mixture of ethyl acetate:methanol (98:2), andthe faster purified fractions combined to afford the desired productwhich is used in the next step without further purification.

Step 2. 3,4-dihydro-5-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-pyrazolinone

Hydrazine monohydrate (0.62 g) is added to a solution of ethyl,3-cyano-3-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-N-morpholino propionate(0.74 g) in ethanol (15 ml). The reaction mixture is heated to refluxfor 221/2 hours, allowed to cool and stand for 48 hours. The mixture isfiltered and the filtered precipitate dried affording the desiredproduct as a light yellow solid. M.P. >280° C.

EXAMPLE IV

When 5-halo-2-picolinic acid or a 2-haloisonicotinic acid is substitutedfor 6-chloronicotinic acid in Step 1 of Example I above, then thecorresponding 5-(1H-imidazol-1-yl)pyrid-2-yl and2-(1H-imidazol-1-yl)pyrid-4-yl products are obtained.

EXAMPLE V

When 1-sodium 1,2,4-triazole is substituted for sodium imidazole in Step2 of Example I above, then the corresponding6-(1,2,4-triazol-1-yl)pyrid-3-yl; 5-(1,2,4-triazol-1-yl)pyrid-2-yl and2-(1,2,4-triazol-1-yl)pyrid-4-yl products are obtained.

EXAMPLE VI Preparation of4,5-dihydro-5-(N-morpholinomethyl)-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3(2H)-pyridazinoneStep 1. 4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-oxo-butanoic acid

A solution of ethyl,4-cyano-4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-N-morpholino butyrate (2.34g, 6.34 mmol) in 14 ml of acetic acid containing 0.9 ml of water isheated to reflux for 1 day. The solvent is removed and the residue isdissolved in CHCl₃ and extracted with saturated aqueous NaHCO₃ solution.The organic layer is then separated, dried (Na₂ SO₄) and evaporated togive crude ethyl 4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-oxo-butanoate.Saponification of the ester in aqueous Na₂ CO₃ at 23° C. generates thedesired product used in the next step without further purification.

Step 2.4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-(N-morpholinomethyl)-4-oxo-butanoicacid

A mixture of 4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-oxo-butanoic acid (1.4g, 5.73 mmol), morpholine (0.5 g), and 37% aqueous formaldehyde (0.46 g)in 3 ml of H₂ O is warmed at 70° C. for 3.5 hours, then stirred at 23°C. for 7 days. The aqueous mixture is extracted with CHCl₃ and reducedin volume to generate a suspension which is filtered to give the desiredproduct used in the next step without further purification.

Step 3.4,5-dihydro-5-(N-morpholinomethyl)-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3(2H)-pyridazinone

A solution of hydrazine monohydrate (0.17 g) and 1.01 g of4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-(N-morpholinomethyl)-4-oxo butanoicacid in ethanol is heated to reflux for 1 day. Upon cooling, a whitesolid precipitates which is filtered to give the desired product.

EXAMPLE VII

Following the procedures of Exmple VI the amines of Table I below may beused in place of morpholine to obtain the corresponding product.

TABLE I

ammonia

ethylamine

diethylamine

methylethylamine

cycolhexylamine

ethyleneimine

trimethyleneimine

piperidine

piperazine

N-methylpiperazine

N-phenylpiperazine

N-benzylpiperazine

N-methylimidazolidine

thiomorpholine

acetamide

EXAMPLE VIII

When hydrazine of the foregoing examples is replaced by the substitutedhydrazine of Table I below then the corresponding product is obtained.

                  TABLE I                                                         ______________________________________                                        NH.sub.2 NHCH.sub.3                                                                              NH.sub.2 NHCONH.sub.2                                      NH.sub.2 NHCH.sub.2 CH.sub.3                                                                     NH.sub.2 NHC(═NH)NH.sub.2                              NH.sub.2 NHCH.sub.2 Ph                                                                           NH.sub.2 NHCONHSO.sub.2 -p-toly                            NH.sub.2 NH(CH.sub.2).sub.2 Ph                                                                   NH.sub.2 NHSO.sub.2 -p-tolyl                               NH.sub.2 NHCOCH.sub.3                                                         NH.sub.2 NHCH.sub.2 CH.sub.2 OH                                               NH.sub.2 NHCH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3                                ______________________________________                                    

Tables I through IV below list representative compounds which are withinthe scope of the present Invention

                  TABLE I                                                         ______________________________________                                         ##STR12##                                                                    R             R.sub.1 R.sup.1  R.sub.2                                                                             R.sub.n                                  ______________________________________                                        H             H       H        H     H                                        H             double bond  H       H                                          H             H       H        H     CH.sub.3                                 CH.sub.3      H       H        H     H                                        CH.sub.3      H       H        H     CH.sub.3                                 CH.sub.3      H       H        H     CH.sub.2 CH.sub.3                        CH.sub.3      H       H        H     CH.sub.2 φ                           CH.sub.3      double bond  H       H                                          CH.sub.3      H       H        CH.sub.3                                                                            H                                        CH.sub.3      H       CH.sub.3 CH.sub.3                                                                            H                                        CH.sub.2 CH.sub.3                                                                           H       H        H     H                                        CH.sub.2 NH.sub.2                                                                           H       H        H     H                                        CH.sub.2 NH.sub.2                                                                           H       H        H     CH.sub.3                                 CH.sub.2 NH.sub.2                                                                           H       H        CH.sub.3                                                                            H                                        CH.sub.2 N(CH.sub.3).sub.2                                                                  H       H        H     H                                        CH.sub.2 N(CH.sub.3).sub.2                                                                  H       H        H     CH.sub.3                                 CH.sub.2 N(CH.sub.3).sub.2                                                                  H       H        CH.sub.3                                                                            H                                        CH.sub.2 N(CH.sub.3).sub.2                                                                  double bond  H       H                                          CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2                                                         H       H        H     H                                         ##STR13##    H       H        H     H                                         ##STR14##    H       H        H     CH.sub.3                                  ##STR15##    double bond  H       H                                           ##STR16##    H       H        CH.sub.3                                                                            H                                         ##STR17##    H       H        CH.sub.3                                                                            CH.sub.3                                  ##STR18##    double bond  CH.sub.3                                                                              H                                           ##STR19##    H       H        H     H                                         ##STR20##    H       H        H     CH.sub.3                                  ##STR21##    H       H        H     CH.sub.2 CH.sub.3                         ##STR22##    H       H        H     CH.sub.2 φ                            ##STR23##    H       H        CH.sub.3                                                                            H                                         ##STR24##    H       H        CH.sub.3                                                                            CH.sub.3                                  ##STR25##    H       CH.sub.3 CH.sub.3                                                                            H                                         ##STR26##    H       CH.sub.3 CH.sub.3                                                                            CH.sub.3                                  ##STR27##    double bond  H       H                                           ##STR28##    H       H        H     H                                         ##STR29##    H       H        H     CH.sub.3                                 CH.sub.2 SH   H       H        H     H                                        CH.sub.2 SCH.sub.3                                                                          H       H        H     H                                        CH.sub.2 SCH.sub.3                                                                          H       H        CH.sub.3                                                                            CH.sub.3                                 CH.sub.2 OH   H       H        H     H                                        CH.sub.2 OCH.sub.3                                                                          H       H        H     H                                         ##STR30##    H       H        H     H                                        ______________________________________                                    

                  TABLE II                                                        ______________________________________                                         ##STR31##                                                                    R                R.sub.1    R.sub.n                                           ______________________________________                                        H                H          H                                                 CH.sub.3         H          H                                                 H                H          CH.sub.3                                          CH.sub.2 CH.sub.3                                                                              H          CH.sub.3                                           ##STR32##       H          H                                                  ##STR33##       H          CH.sub.3                                           ##STR34##       H          CH.sub.3                                           ##STR35##       H          CH.sub.2 CH.sub.3                                  ##STR36##       H          CH.sub.2 φ                                    CH.sub.3         CH.sub.3   CH.sub.3                                          ______________________________________                                    

                  TABLE III                                                       ______________________________________                                         ##STR37##                                                                    R              R.sub.1 R.sup.1 R.sub.2                                                                              R.sub.n                                 ______________________________________                                        H              H       H       H      H                                       H              double bond     H      H                                       CH.sub.3       H       H       H      H                                       CH.sub.2 CH.sub.3                                                                            H       H       H      H                                       CH.sub.3       H       H       H      CH.sub.3                                 ##STR38##     H       H       H      H                                        ##STR39##     H       H       H      H                                        ##STR40##     H       H       H      CH.sub.3                                 ##STR41##     H       H       CH.sub.3                                                                             CH.sub.3                                ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                         ##STR42##                                                                    R              R.sub.1 R.sup.1  R.sub.2                                                                             R.sub.n                                 ______________________________________                                        H              H       H        H     H                                       CH.sub.3       H       H        H     CH.sub.3                                H              H       H        H     CH.sub.3                                 ##STR43##     H       H        H     CH.sub.3                                ______________________________________                                    

The compounds of Formula I possess positive inotropic activity and areuseful as cardiotonic agents in the treatment of humans and othermammals for cardiac disorders including congestive heart failure. Theeffectiveness of the compounds of this invention as inotropic agents maybe determined by the following pharmacologic tests which evaluate thechange in cardiac contractile force upon exposure to a dose of saidcompounds. The anesthetized dog procedure is a standard test procedure;the inotropic results of this procedure generally correlate with theinotropic activity found in human patients.

Anesthetized Dog Procedure

Male mongrel dogs are anesthetized with pentobarbital (35 mg/kg i.v.)and intubated. Femoral artery and veins are cannulated for measurementof blood pressure and injection of compounds, respectively. A catheterconnected to a Statham transducer is inserted into the left ventriclevia the right carotid artery for measurement of left ventricularpressure, left ventricular and diastatic pressure and dP/dt. Lead II ECGand heart rate are also monitored. All parameters are measured on aBeckman Dynagraph.

Two additional test procedures which have been found to be an efficientmeans for ascertaining the inotropic activity of the compounds of thisinvention are described below.

Conscious Instrumented Dog

Female mongrel dogs (18.9-18.5 kg) are anesthetized with sodiumpentobarbital (35 mg/kg i.v., supplemented as necessary during surgery)intubated and connected to a Harvard respirator. The left side of thechest is opened at the fifth intercostal space, and a Konigsbergtransducer inserted into the left ventricle through a puncture at theapex and secured. A fluid-filled polyethylene catheter is inserted intothe left atrium through a puncture wound and secured for measurement ofleft atrial pressure. A second fluid-filled catheter is inserted intothe aorta for measurement of blood pressure and heart rate and securedto the vessel wall. The two catheters and the Konigsberg transducercable are passed out of the chest through the seventh intercostal spaceand advanced subcutaneously to the back of the neck and passed throughthe skin. The fluid-filled catheters are filled with heparnized 50%dextrose solution, and the chest is closed and evacuated.

The dogs are treated daily post-operatively with 600,000 units ofpenicillin-procaine i.m. for ten days and with chloramphenicol, 500mg/kg i.m., every other day for 10 days and allowed at least 7 daysrecovery before use.

Each dog is trained and acclimated to her environment and the presenceof personnel during the experiment.

The dogs are fasted overnight before either intravenous or oraladministration of the compound. On a test day, the dog is placed in asling and connected to a recorder (Gould Instruments or GrassInstruments) for measurement of left ventricular pressure, leftventricular end diastolic pressure, left ventriuclar dP/dt_(max), bloodpressure, heart rate (from the blood pressure signal), and the lead IIelectrocardiogram. The compound is administered both intravenously andorally (liquid and soft gelatin capsule forms) in different experimentsand blood samples were taken for determination of blood levels of thecompound.

Guinea Pig Atria Inotropic Screening at Low Calcium Concentrations

Guinea pigs are stunned by a sudden blow to the head; their chests areopened and hearts excised and placed in Kreb's medium (concentrations,mM: NaCl, 118.39; KCl, 4.70; MgSO₄, 1.18; KH₂ PO₄, 1.18; NaHCO₃ ; 25.00;glucose, 11.66; and CaCl₂, 1.25) gassed with a mixture of 95% O₂ 5% CO₂.Left atria are removed and inserted into warmed 33° C. double jacketedtissue chambers containing oxygenated Kreb's medium (as above). Theupper end of each tissue is attached to a Statham Universal TransducingCell via a Statham Microscale Accessory. Resting tension on each tissueis set at 1 g and adjusted periodically.

Massive field stimulation is achieved via a pair of platinum or silverelectrodes placed on opposite sides of the tissue. Electrodes are madefrom 20 gauge silver wire wound into a tight coil approximately 12-14 mmin diameter. Electrodes are connected to a Grass stimulator via Grassconstant current unit. Tissues are driven at 90 pulses per minute with a5 msec duration at current levels 20% greater than threshold forcontinuous beat.

Cumulative concentrations of test drugs are added to the tissue bath atintervals sufficient to allow developed tension to peak at a new level.

The increase in developed tension in each tissue for each compoundconcentration is measured, and the results are averaged and used toconstruct cumulative concentration-response curves. Slopes for theseregressions are calculated via the method of Finney (1971) and comparedusing Student's t-test.

The compounds of this invention can be normally administered orally orparenterally, in the treatment of cardiac disorders such as heartfailure in humans or other mammals.

The compounds of this invention, preferably in the form of a salt, maybe formulated for administration in any convenient way, and theinvention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Suitable carriers include diluents or fillers,sterile aqueous media and various non-toxic organic solvents. Thecompositions may be formulated in the form of tablets. capsules,lozenges, troches, hard candies, powders, aqueous suspensions, orsolutions, injectable solutions, elixirs, syrups and the like and maycontain one or more agents selected from the group including sweeteningagents, flavoring agents, coloring agents and preserving agents, inorder to provide a pharmaceutically acceptable preparation.

The particular carrier and the ratio of inotropic active compound tocarrier are determined by the solubility and chemical properties of thecompounds, the particular mode of administration and standardpharmaceutical practice. For example, excipients such as lactose, sodiumcitrate, calcium carbonate and dicalcium phosphate and variousdisintegrants such as starch, alginic acid and certain complexsilicates, together with lubricating agents such as magnesium stearate,sodiumlauryl sulphate and talc, can be used in producing tablets. For acapsule form, lactose and high molecular weight polyethylene glycols areamong the preferred pharmaceutically acceptable carriers. Where aqueoussuspensions for oral use are formulated, the carrier can be emulsifyingor suspending agents. Diluents such as ethanol, propylene glycol,glycerin and chloroform and their combinations can be employed as wellas other materials.

For parenteral administration, solutions or suspensions of thesecompounds in sesame or peanut oil or aqueous propylene glycol solutions,as well as sterile aqueous solutions of the soluble pharmaceuticallyacceptable salts described herein can be employed. Solutions of thesalts of these compounds are especially suited for intramuscular andsubcutaneous injection purposes. The acqueous solutions, including thoseof the salts dissolved in pure distilled water, are also useful forintravenous injection purposes, provided that their pH is properlyadjusted, suitably buffered, made isotonic with sufficient saline orglucose and sterilized by heating or by microfiltration.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective inincreasing the contractile force of the heart or in the treatment ofcardiac failure. In general, the oral dose may be between about 0.01mg/kg and about 50 mg/kg (preferably in the range of 0.1 to 10 mg/kg),and the i.v. dose about 0.005 to about 30 mg/kg (preferably in the rangeof 0.01 to 3 mg/kg), bearing in mind, of course, that in selecting theappropriate dosage in any specific case, consideration must be given tothe patient's weight, general health, age, and other factors which mayinfluence response to the drug. The drug may be administered orally 1 to4 times per day, preferably twice daily.

We claim:
 1. A compound of the formula: ##STR44## where: Het isimidazol-1-yl or 1,2,4-triazol-1-yl;R_(n) is hydrogen, alkyl, aralkyl,acetyl, propionyl, benzoyl, carbalkoxy, carbamyl, carbalkoxyalkyl,hydroxyalkyl, alkoxyalkyl or amidino; R₁ is hydrogen, alkyl or aralkyl;and R is hydrogen or --(CH₂)_(y) --Y where y is 1-3 and Y is hydrogen,--O--R.sub.α' --S--R.sub.α or ##STR45## where R.sub.α is hydrogen, alkylor acetyl, propionyl, benzoyl and; R.sub.β is hydrogen or alkyl; andR.sub.α and R.sub.β together with the nitrogen to which they areattached may form a 3 to about 6 membered ring selected from the groupconsisting of aziridinyl, azetidinyl, piperidyl, N-methylimidazolidinyl,piperazinyl, substituted piperazinyl where the substituent maybeN-methyl, N-benzyl or N-phenyl, morpholinyl or thiomorpholinyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 where the pyridyl ring is bonded to the pyrazolone ring at the2-pyridyl carbon position.
 3. A compound according to claim 1 where thepyridyl ring is bonded to the pyrazolone ring at the 3-pyridyl carbonposition.
 4. A compound according to claim 1 where the pyridyl ring isbonded to the pyrazolone ring at the 4-pyridyl carbon position.
 5. Acompound according to claim 3 where Het is imidazoyl-1-yl.
 6. A compoundaccording to claim 3 where Het is 1,2,4-triazol-1-yl.
 7. A compoundaccording to claim 5 where R is hydrogen or --(CH₂)_(y) --Y where y is1-3 and Y is hydrogen.
 8. A compound according to claim 5 where R is##STR46## where R.sub.α and R.sub.β are hydrogen or alkyl.
 9. A compoundaccording to claim 5 where R is ##STR47## where R.sub.α and R.sub.βtogether with the nitrogen to which they are attached form a 3 to about6 membered ring selected from the group consisting of aziridinyl,azetidinyl, piperidyl, N-methylimidazolidinyl, piperazinyl, substitutedpiperazinyl where the substituent may beN-methyl, N-benzyl or N-phenyl,morpholinyl or thiomorpholinyl.
 10. A pharmaceutical composition forincreasing cardiac contractility in a human or other animal requiringsuch treatment comprising an effective amount of a compound according toclaim 1 in admixture with a pharmaceutically acceptable carrier.
 11. Amethod for increasing cardiotonic contractility in a human or othermammal requiring such treatment which comprises administering thereto aneffective inotropic amount of a compound of the formula: ##STR48##where: Het is imidazol-1-yl or 1,2,4-triazol-1-yl;R_(n) is hydrogen,alkyl, aralkyl, acetyl, propionyl, benzoyl, carbalkoxy, carbamyl,carbalkoxyalkyl, hydroxyalkyl, alkoxyalkyl or amidino; R₁ is hydrogen,alkyl or aralkyl; and R is hydrogen or --(CH₂)_(y) --Y where y is 1-3and Y is hydrogen, --O--R_(a') --S--R.sub.α or ##STR49## where R.sub.αis hydrogen, alkyl or acetyl, propionyl, benzoyl and; R.sub.β ishydrogen or alkyl; and R.sub.α and R.sub.β together with the nitrogen towhich they are attached may form a 3 to about 6 membered ring selectedfrom the group consisting of aziridinyl, azetidinyl, piperidyl,N-methylimidazolidinyl, piperazinyl, substituted piperazinyl where thesubstituent may beN-methyl, N-benzyl or N-phenyl, morphonlinyl orthiomorpholinyl; or a pharmaceutically acceptable salt thereof.
 12. Acompound according to claim 9 which forms a N-piperazinyl ring.
 13. Acompound according to claim 9 which forms a N-morpholino ring.
 14. Acompound according to claim 9 which forms a N-piperdinyl ring.
 15. Acompound according to claim 13 where R_(n) and R₁ are all hydrogen. 16.A compound according to claim 13 where at least one of R_(n) and R₁ ishydrogen.
 17. A compound according to claim 15 which is2,4-dihydro-4-(N-morpholinomethyl)-5-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-pyrazolone.18. A compound according to claim 16 which is2,4-dihydro-4-(N-morpholinomethyl)-4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-2-methyl-3-pyrazolone.19. A compound according to claim 7 which is2,4-dihydro-4,4-dimethyl-5-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3-pyrazolone.